title: Regulation of calcium channels and exocytosis in mouse adrenal chromaffin cells by prostaglandin EP3 receptors.
abstract: Prostaglandin (PG) E(2) controls numerous physiological functions through a family of cognate G protein-coupled receptors (EP1-EP4). Targeting specific EP receptors might be therapeutically useful and reduce side effects associated with nonsteroidal anti-inflammatory drugs and selective cyclooxygenase-2 inhibitors that block prostanoid synthesis. Systemic immune challenge and inflammatory cytokines have been shown to increase expression of the synthetic enzymes for PGE(2) in the adrenal gland. Catecholamines and other hormones, released from adrenal chromaffin cells in response to Ca(2+) influx through voltage-gated Ca(2+) channels, play central roles in homeostatic function and the coordinated stress response. However, long-term elevation of circulating catecholamines contributes to the pathogenesis of hypertension and heart failure. Here, we investigated the EP receptor(s) and cellular mechanisms by which PGE(2) might modulate chromaffin cell function. PGE(2) did not alter resting intracellular [Ca(2+)] or the peak amplitude of nicotinic acetylcholine receptor currents, but it did inhibit Ca(V)2 voltage-gated Ca(2+) channel currents (I(Ca)). This inhibition was voltage-dependent and mediated by pertussis toxin-sensitive G proteins, consistent with a direct Gβγ subunit-mediated mechanism common to other G(i/o)-coupled receptors. mRNA for all four EP receptors was detected, but using selective pharmacological tools and EP receptor knockout mice, we demonstrated that EP3 receptors mediate the inhibition of I(Ca). Finally, changes in membrane capacitance showed that Ca(2+)-dependent exocytosis was reduced in parallel with I(Ca). To our knowledge, this is the first study of EP receptor signaling in mouse chromaffin cells and identifies a molecular mechanism for paracrine regulation of neuroendocrine function by PGE(2).
authors.affiliation: Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, TN 37232-2520, USA.
authors.forename: Mark L
authors.initials: ML
authors.lastname: Jewell
authors.forename: Richard M
authors.initials: RM
authors.lastname: Breyer
authors.forename: Kevin P M
authors.initials: KP
authors.lastname: Currie
mesh_terms: D000818:Animals; D001483:Base Sequence; D015220:Calcium Channels / Q000502:physiology*; D019439:Chromaffin Cells / Q000378:metabolism*; D017931:DNA Primers; D015232:Dinoprostone / Q000494:pharmacology; D005089:Exocytosis / Q000502:physiology*; D008297:Male; D051379:Mice; D012333:RNA, Messenger / Q000235:genetics; D011982:Receptors, Prostaglandin / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D015220:Calcium Channels; D017931:DNA Primers; D012333:RNA, Messenger; D011982:Receptors, Prostaglandin; D015232:Dinoprostone